Endocrinology Research Analysis
Q1 2025 endocrinology was shaped by inter-organ and neuroendocrine circuit discoveries, foundational human atlases/portals, and translational advances targeting remission and prevention. A Science study repositioned myostatin as an endocrine driver of FSH, while a Nature human hypothalamus atlas and paired circuit papers (thalamic mu-opioid sugar appetite, sleep-induced Raptin–GRM3 axis) reframed appetite control. A liver-to-brain vagal sensory pathway causally linked steatosis, energy expenditu
Summary
Q1 2025 endocrinology was shaped by inter-organ and neuroendocrine circuit discoveries, foundational human atlases/portals, and translational advances targeting remission and prevention. A Science study repositioned myostatin as an endocrine driver of FSH, while a Nature human hypothalamus atlas and paired circuit papers (thalamic mu-opioid sugar appetite, sleep-induced Raptin–GRM3 axis) reframed appetite control. A liver-to-brain vagal sensory pathway causally linked steatosis, energy expenditure, and anxiety, converging with neuroendocrine findings. Microbiome–immune–endocrine work identified Aspergillus tubingensis and its AhR-antagonist metabolite as a causal PCOS driver, and complementary mouse data showed preconception caloric restriction can block intergenerational PCOS transmission via oocyte methylation. Infrastructure matured with an adipose multi-omics portal enabling cross-cohort, single-cell–aware analyses; cross-disciplinary virology identified APOBEC-1 cofactors as regulators of HBV mutagenesis. A multicentre RCT showed dapagliflozin plus structured calorie restriction raises 12‑month T2D remission, offering a scalable clinical pathway.
Selected Articles
1. Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis.
Mouse studies demonstrate myostatin acts systemically as an endocrine hormone to directly stimulate pituitary FSH synthesis, establishing a skeletal muscle–pituitary axis and challenging activin’s primacy in FSH regulation.
Impact: Redefines reproductive hormonal hierarchies and raises immediate safety/efficacy considerations for myostatin-targeting therapeutics.
Clinical Implications: Myostatin antagonism (in development for muscle disorders) may affect fertility; monitoring and counseling should be considered.
Key Findings
- Myostatin directly promotes pituitary FSH synthesis in vivo.
- Establishes a skeletal muscle–pituitary endocrine axis challenging activin primacy.
- Therapeutic myostatin antagonism may have unintended fertility effects.
2. A comprehensive spatio-cellular map of the human hypothalamus.
This study builds a foundational spatio-cellular atlas of the human hypothalamus, mapping neuroendocrine cell types and their spatial organization to enable mechanistic interrogation of circuits that control appetite, thermoregulation, reproduction, and pituitary axes.
Impact: It provides the first high-resolution human resource linking cell types, spatial context, and function in neuroendocrine control, accelerating target discovery and translational research.
Clinical Implications: Enables identification of tissue- and cell-specific therapeutic targets and biomarkers for hypothalamic disorders and informs neuromodulation strategies.
Key Findings
- Generated a comprehensive atlas delineating hypothalamic cell types and spatial relationships.
- Supports mechanistic interrogation of circuits relevant to appetite, thermoregulation, reproduction, and pituitary regulation.
- Links spatial context to function, facilitating precise target discovery in human neuroendocrinology.
3. The intestinal fungus Aspergillus tubingensis promotes polycystic ovary syndrome through a secondary metabolite.
Multi‑cohort human profiling identified enrichment of Aspergillus tubingensis in PCOS patients; mouse colonization recapitulated PCOS‑like reproductive and metabolic phenotypes by inhibiting AhR signaling and reducing ILC3-derived IL‑22. A strain-diversity metabolite screen pinpointed AT‑C1, an endogenous fungal AhR antagonist, as the causal metabolite—establishing a mycobiome→AhR→immune axis driving PCOS.
Impact: First mechanistic demonstration that a specific gut fungus and its metabolite causally drive PCOS via immune (AhR/ILC3/IL‑22) signaling—opens a new etiologic paradigm and target space for microbiome- and AhR-modulating therapies.
Clinical Implications: Supports investigating gut mycobiome profiling in PCOS patients and testing interventions that restore AhR signaling or deplete pathogenic fungal strains/metabolites as adjuncts to metabolic and ovulatory therapies.
Key Findings
- Aspergillus tubingensis is enriched in PCOS cohorts across three regions (n=226).
- Colonization with A. tubingensis induces PCOS-like phenotypes in mice by inhibiting AhR signaling and reducing ILC3-derived IL‑22.
- AT‑C1, a fungal metabolite, acts as an endogenous AhR antagonist mediating the phenotype.
4. Raptin, a sleep-induced hypothalamic hormone, suppresses appetite and obesity.
This cross-species mechanistic study identifies Raptin, a peptide cleaved from RCN2 and secreted during sleep, that binds GRM3 in hypothalamic and gastric neurons to suppress appetite and delay gastric emptying via PI3K–AKT signaling; human data link impaired Raptin secretion to night eating and obesity.
Impact: It defines a novel, druggable endocrine axis directly linking sleep physiology to appetite control (Raptin–GRM3), expanding therapeutic avenues for obesity and sleep-related metabolic disorders.
Clinical Implications: Prioritizes sleep optimization as a metabolic intervention and nominates GRM3/Raptin signaling for drug development, including potential Raptin analogs or GRM3 agonists pending safety.
Key Findings
- Raptin is cleaved from RCN2 and peaks during sleep via an SCN(AVP+)→PVN circuit.
- Raptin binds GRM3 in hypothalamic and gastric neurons to suppress appetite and slow gastric emptying via PI3K–AKT signaling.
- Human genetic/phenotypic data link impaired Raptin signaling with night eating syndrome and obesity.
5. adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue.
This curated, publicly accessible portal aggregates clinical and experimental transcriptomic/proteomic datasets from more than 6,000 individuals across depots, cell types, and perturbation studies, enabling reproducible cross-study and single-cell–level adipose analyses.
Impact: It provides foundational infrastructure to standardize and democratize large-scale human adipose datasets, accelerating discovery of adipose biology, biomarkers, and therapeutic targets across obesity and metabolic disease.
Clinical Implications: While indirect, the portal enables rapid validation of adipose-derived biomarkers and targets that can translate to diagnostics or therapies for insulin resistance, NAFLD, and obesity when integrated into translational pipelines.
Key Findings
- Centralizes and harmonizes clinical and experimental adipose transcriptomic/proteomic data from >6,000 individuals.
- Supports multi-depot, cell-type, and perturbation study integration down to single-cell resolution.
- Provides standardized public access and tools enabling reproducible cross-cohort analyses.
6. Thalamic opioids from POMC satiety neurons switch on sugar appetite.
In mice, hypothalamic POMC satiety neurons paradoxically activate a projection to the paraventricular thalamus that engages mu-opioid signaling to promote sugar intake in sated states; inhibition of this circuit reduces high-sugar consumption.
Impact: It reveals a targetable neuroendocrine microcircuit linking satiety to hedonic sugar intake, reframing mechanisms of overeating and pointing to new anti-obesity interventions.
Clinical Implications: Suggests neuromodulatory or pharmacologic strategies aimed at the thalamic mu-opioid pathway to curb sugar-driven overeating without broadly suppressing appetite.
Key Findings
- POMC neurons promote satiety yet activate sugar appetite via a POMC→paraventricular thalamus projection.
- The projection inhibits postsynaptic neurons through mu-opioid receptor signaling during sugar consumption in sated animals.
- Circuit inhibition reduces high-sugar intake without broadly diminishing general appetite.
7. Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice.
Selective ablation of liver-projecting vagal sensory neurons increased energy expenditure, prevented diet-induced obesity, attenuated hepatic steatosis, improved glucose homeostasis (with male-specific insulin sensitivity gains), and reduced anxiety-like behavior—defining a causal liver→brain neural pathway.
Impact: Reveals a discrete, targetable organ→brain circuit linking steatosis, energy balance, and behavior, opening neuromodulation strategies for MAFLD/obesity with neuropsychiatric comorbidity.
Clinical Implications: Motivates translational development of neuromodulatory therapies (afferent modulation/devices) and biomarkers to quantify liver→brain signaling in human obesity and MAFLD.
Key Findings
- Ablation of liver-projecting vagal sensory neurons prevents diet-induced obesity by increasing energy expenditure.
- Loss of these neurons limits hepatic steatosis and improves glucose homeostasis; males show increased insulin sensitivity.
- Neuronal loss reduces anxiety-like behavior, implicating the liver–brain axis in behavioral regulation.
8. APOBEC-1 cofactors regulate APOBEC3-induced mutations in hepatitis B virus.
Using HBV cellular replication models, the authors show that APOBEC‑1 cofactors and associated hnRNPs physically associate with APOBEC3 proteins to enhance their mutational activity; disruption by siRNA or mutagenesis markedly reduces A3 activity, and A1 cofactors promote A3C access to HBV (−)DNA producing kataegis‑like hypermutation.
Impact: Reveals a cell-intrinsic regulatory mechanism for APOBEC3 mutagenesis that links antiviral immunity and cancer mutagenesis, identifying modifiable host factors (A1 cofactors/hnRNPs) as potential therapeutic or biomarker targets.
Clinical Implications: Guides strategies to limit APOBEC‑driven tumor mutagenesis or enhance antiviral restriction by targeting APOBEC‑1 cofactor/hnRNP interactions; informs biomarker development for A3 activity in HBV and possibly oncology.
Key Findings
- APOBEC‑1 cofactors and hnRNPs strongly interact with APOBEC3 proteins and enhance A3 mutational activity in HBV replication systems.
- Disruption (siRNA or mutagenesis) of A3–hnRNP interactions markedly reduces mutagenesis.
- A1 cofactors increase A3C accessibility to HBV (−)DNA and promote kataegis‑like hypermutation patterns.
9. Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial.
A multicentre double‑blind RCT in China (n=328) found dapagliflozin 10 mg/day plus structured calorie restriction led to 44% diabetes remission at 12 months versus 28% with calorie restriction plus placebo (RR 1.56), with greater reductions in weight, HOMA‑IR and metabolic risk factors and no excess adverse events.
Impact: High‑quality randomized evidence that adding an SGLT2 inhibitor to dietary restriction increases remission rates provides a practical, scalable strategy for remission‑oriented diabetes care and informs guideline development.
Clinical Implications: Consider SGLT2 inhibitor plus structured calorie restriction for overweight/obese patients with early T2D aiming for remission, with individualized monitoring for metabolic effects and durability assessment over longer follow-up.
Key Findings
- 12-month remission: 44% with dapagliflozin + calorie restriction vs 28% with calorie restriction alone (RR 1.56).
- Greater reductions in body weight (−1.3 kg difference) and HOMA‑IR, with improved body fat and systolic BP.
- No significant increase in adverse events compared with placebo over 12 months.
10. Caloric restriction prevents inheritance of polycystic ovary syndrome through oocyte-mediated DNA methylation reprogramming.
Using IVF-ET and surrogacy in mouse models, oocytes from androgen-exposed females transmitted PCOS-like traits across generations, whereas parental caloric restriction restored oocyte DNA methylation at insulin secretion and AMPK pathway genes and prevented transmission; supportive signals were noted in human embryonic methylomes.
Impact: It proposes a modifiable preconception intervention that blocks epigenetic transmission of metabolic disease risk, reframing prevention strategies for PCOS.
Clinical Implications: Supports counseling and trials of preconception metabolic optimization for women with PCOS, with potential to reduce intergenerational disease burden if translatable.
Key Findings
- Oocytes from androgen-exposed mice transmitted PCOS-like traits to F2/F3 via IVF-ET/surrogacy.
- Caloric restriction in parental generations restored disrupted oocyte DNA methylation in insulin secretion/AMPK genes and prevented transmission.
- Findings motivate structured preconception interventions and human trials to prevent intergenerational PCOS risk.